Process for preparing gamma-cyhalothrin

ABSTRACT

A process for the preparation of gamma-cyhalothrin comprising steps of a) chlorinating 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid to give 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride and b) esterifying 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride with the (S)-cyanohydrin of 3-phenoxy benzaldehyde (III).

The present invention relates to a process for making insecticidalcyclopropanecarboxylic acid esters. More particularly, the inventionrelates to a process for making gamma-cyhalothrin[(S)-α-cyano-3-phenoxybenzyl(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate].

It is well known that the insecticidal activity of pyrethroids such ascyclopropanecarboxylic acid esters e.g. cyhalothrin is greatly affectedby their stereochemistry. It is disclosed in Bentley et al, Pestic. Sci.(1980), 11(2), 156-64) that (S)-α-cyano-3-phenoxybenzyl(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylateis the most active isomer of cyhalothrin.

In order to produce gamma-cyhalothrin on an industrial scale it isdesirable to find methods of making the final product that avoid the useof expensive reagents and have as few chemical stages as possible. Thepresent invention provides a direct process to meet these requirements.There is therefore provided a process for the preparation ofgamma-cyhalothrin (IV) comprising a) chlorinating 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid (I) to give 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (II) and b) esterifying 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (II) with the (S)-cyanohydrin of3-phenoxy benzaldehyde (III).

1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid (I) is a known compound and its preparationis described for example in U.S. Pat. No. 4,683,089, WO02/06202,WO97/03941 and WO/9942432.

Step a) is performed by standard techniques as in ‘March 4^(th)Edition—p437-38’. Preferred chlorinating agents are thionyl chloride,phosgene or phosphorous oxychloride. Preferred solvents are hydrocarbonssuch as toluene, hexane, heptane or fluorobenzene. Preferredtemperatures are from ambient to 100° C. or the boiling point of thesolvent.

Preferably the acid (I) has an enantiomeric purity of greater than 80%of 1R 3R enantiomer, and more preferably greater than 90% 1R 3Renantiomer.

Step b) is performed in the presence of a solvent or in the absence of asolvent, in which case the molten product can act as the reactionmedium. The reaction can be carried out in a single organic phase or ina mixture of a water immiscible organic phase and an aqueous phase. Theacid chloride, either neat or in a solvent, may be added to thecyanohydrin, or the vice versa, but it is preferable to add the acidchloride to the cyanohydrin. The mol ratio of the reactants ispreferably 1:1 but up to 10 mol % excess of either reactant can beemployed, but most preferably the excess of one reactant over the otheris 1-5 mol %.

On an industrial scale it is highly desirable that the reaction is takento completion (where, in the case of 1:1 stoichiometry of reactants,completion means there is a residual level of both acid chloride andcyanohydrin of <5% by weight and preferably <1% by weight, and where onereactant is used in excess of the other, the residual level of the minorreactant is <1% preferably <0.2%) to maximize the yield.

In known esterification processes for making other pyrethroids (e.g.EP109681, U.S. Pat. No. 4,252,820, EP3336A1, U.S. Pat. No. 4,258,202,WO0206202, GB2000764, U.S. Pat. No. 4,343,677 and U.S. Pat. No.5,164,411) taking the reaction to completion has not been attempted orhas been attempted either by performing the reaction in the presence ofa stoichiometric amount of an organic base (e.g. U.S. Pat. No.4,258,202) or by physical removal of the HCl as it is formed byconducting the reaction at the boiling point of the solvent (e.g. U.S.Pat. No. 5,164,411). However neither of these processes is satisfactory.The use of stoichiometric amounts of a base is undesirable as thisnecessitates a complicated recovery process to avoid the cost ofdisposing of the base. When using physical removal of HCl as a means ofprogressing the esterification reaction, the applicants have found thatit is difficult to consume the last few % of the reactants withoutsignificantly extending the reaction time. Surprisingly the reaction canbe taken to completion within an acceptable time by removal of HCl fromthe reaction using a combination of physical methods and asub-stoichiometric amount of a base.

Therefore in one aspect of the invention there is provided a process inwhich HCl formed during the esterification is removed from the reactionmass using a combination of physical methods and a sub-stoichiometricamount of a base.

Physical removal of co-product HCl can be accomplished by conducting thereaction at the boiling point of the solvent or by continuous removal ofthe solvent by distillation whilst adding fresh solvent to replace thatwhich has been distilled out or by application of vacuum or by spargingthe reaction mass with an inert gas such as nitrogen or by the presenceof a separate water phase that can extract the HCl, or by anycombination of these procedures. The base can be either an organic base,such as a tertiary amine, or an inorganic base such as an alkali metalcarbonate or bicarbonate or alkaline earth metal oxide, hydroxide orcarbonate or a combination of an organic and an inorganic base. In thelatter case, the organic base serves to facilitate the reaction of theHCl formed in the reaction with the heterogeneous inorganic base.

The base may be added from the outset or may be added during the courseof the reaction but is preferably added once the reaction has been takento >50% by physical removal of HCl and most preferably after thereaction is >80% completed.

The applicants have found that addition of the base late on in thereaction has the advantage of minimising impurity formation andmaximizing yield.

Preferred organic bases have a pKa of between 2 and 7 and morepreferably between 3 and 6. Particularly preferred organic bases arepyridine, alkylpyridines, quinoline, the trimethylether oftriethanolamine or the mono-hydrochloride salt of DABCO(1,4-diazabicyclo[2.2.2]octane). The base can be used at <0.8equivalents on the acid chloride, preferably <0.5 equivalents and mostpreferably between 0.1-0.25 equivalents. When an organic and aninorganic base are combined, it is desirable to have the inorganic baseas the major component of the binary mixture and the organic base as theminor component. Thus the organic base is preferably <50% and mostpreferably <10% of the total molar amount of base used in the reaction.

Suitable solvents for the reaction are aliphatic or aromatichydrocarbons. Examples of aromatic hydrocarbons are toluene, o-xylene,mixed xylenes or halobenzenes, for example fluorobenzene. Aliphatichydrocarbons are for example hexane, cyclohexane, iso-hexane, heptane,octane or mixtures of hydrocarbons commonly known as petroleum ethers.Preferred solvents are hexane, cyclohexane, iso-hexane, heptane oroctane.

In a preferred embodiment of the invention, the same solvent is used inboth steps a) and b). Suitable temperatures for the reaction are in therange 20-120° C., preferably 60-80° C.

In a further aspect of the invention, the esterification can be carriedout in a two-phase system in which one phase is an aqueous phase andoptionally in the presence of an organic base that may act as a reactionpromoter. The aqueous phase serves to help extract the HCl as it formsfrom the organic phase and the pH of the aqueous phase can be maintainedat a desired level by addition of base to neutralize the HCl as itforms. The preferred pH of the aqueous phase is pH 3-10 but preferablypH 6-8. The pH can be maintained by continuous addition of an inorganicbase, for example sodium or potassium hydroxide, and the use of a ‘pHstat’, which will control the pH automatically. The pH control isoptionally carried out in the presence of a buffer, which helps to avoidlarge swings in the pH. Suitable buffers are borate or phosphate salts.Suitable reaction promoters are organic bases such as pyridine or alkylpyridines.

On completion of the reaction, any base, along with salts formed in thereaction, can be removed by washing the product with dilute mineralacid. Optionally this can be carried out at elevated temperature tohydrolyse any residual acid chloride, or any acid anhydride formed inthe reaction, to the carboxylic acid. The carboxylic acid can then beremoved from the product by washing with water that has a pH maintainedin the region of pH 5-8 and preferably pH 6-7. This can be accomplishedby the use of an appropriate buffer and controlled addition of a base,for example sodium or potassium dihydrogen phosphate and sodium orpotassium hydroxide. Finally, the product is washed with dilute acid toprevent epimerisation at the benzylic position and any solvent isremoved by conventional methods. The product can then be purifiedfurther if required by, for example, recrystallisation.

Alternatively, the product can be crystallised directly from thereaction solvent. In this case, the preferred reaction solvents arealiphatic hydrocarbons. In a preferred embodiment of the invention, thesame solvent is used in steps a) and b) of the process and in the finalpurification.

The following Examples illustrate the invention.

The products were analysed by Gas Chromatography using an Agilent gaschromatograph with a Chrompack CP Sil 5 CB column (50 metres, 0.32 mm IDand 0.1 μm film thickness) with helium as carrier, split injection at 15psi. Injection temperature 300° C. detector 325° C. and a detector gascomposition of hydrogen 30 ml/min, air 350 ml/min and helium at 30ml/min). The oven temperature profile was: initial temp 50° C., initialtime 6 mins then heating rate 10° C. min to 120° C. and hold for 3 minsthen ramp to 240° C. at 25° C./min. Hold for 8 minutes then ramp to 300°C. at 50° C. and hold for 6 minutes to burn off the column.

Using these conditions, the following retention times were observed:

-   (S)-α-cyano-3-phenoxybenzyl    (Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate    (gamma-cyhalothrin) 27.4 mins-   (R)-α-cyano-3-phenoxybenzyl    (Z)-(1R,3R-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate    27.0 mins

EXAMPLE 1 Preparation of 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropanecarboxylic acid chloride

A 1 litre dry, clean jacketed split reaction vessel equipped withagitator, thermometer, condenser, nitrogen blanket and vent to ascrubber system was charged with toluene (450 ml) and agitated whilst 1Rcis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropanecarboxylic acid (89.4 gm=0.369 mol) was added followed by triethylamine(0.21 gm=2.1 mmol). The reaction mixture was then heated to 45° C.,using oil circulation on the jacket, and thionyl chloride (62.0 gm=0.52mol) was then charged over 105 minutes maintaining on temperature. Thereaction mass was then agitated for 5 hours at 45° C. then tested by GLCfor completion of reaction showing 2% residual acid. A further additionof thionyl chloride (4.4 gm=37 mmol) was then made and the reaction massallowed to cool with stirring overnight. The following day, residualthionyl chloride, dissolved sulphur dioxide and hydrogen chloride gaseswere removed by distillation of about 320 ml toluene under vacuum. GC,GCMS and NMR analysis of the product were consistent with the structureof the acid chloride (IIIa). Yield, 175 gm of a 54% solution of the acidchloride in toluene, 97% theory. α_(D)=+46° (c=0.012, DCM).

EXAMPLE 2 Thermal Coupling of((1R,3S)-3-((Z)-2-Chloro-propenyl)-2,2-dimethyl-cyclopropanecarbonylchloride to (S)-3-phenoxybenzaldehyde cyanohydrin with DistillativeRemoval of HCl and Completion with Pyridine

The acid chloride (II) (5 gm 23 millimol) and cyclohexane (25 ml) wereadded to a dry 100 ml 3 necked round bottomed flask fitted with magneticstirrer bar, short path distillation equipment (vented to a causticscrubber system), thermometer and nitrogen blanket. The reactor contentswere agitated and heated to 80° C. Distillation was started and theS-cyanohydrin (5.06 gm @ 90%=20 millimol), dissolved in a littlecyclohexane, was then added over approximately 1 hour. Cyclohexane wasthen continually added at the same rate as the loss of cyclohexane bydistillation. After 3.5 hours, GC analysis showed that most of the acidchloride had been consumed. A further charge of acid chloride was made(0.35 gm 1.3 millimol) and the reaction mixture allowed to cool and stirovernight. A further addition of acid chloride (0.7 gm 2.6 millimol) wasmade and refluxing continued for 21 hrs after which time there was still1.9 area % acid chloride in the reaction mass.

Pyridine (0.05 gm 0.6 millimol) and S-cyanohydrin were added (0.314 gm1.3 millimol), and the reaction mass was refluxed for 3 hrs then allowedto cool to room temperature. GC analysis showed the acid chloride levelto be 0.1%. The reaction mass was then worked up by the addition ofhexane (40 ml) which promoted crystallisation on stirring. The resultantwhite solid was separated from the solvent by filtration and washed withhexane (2×5 ml), water (5 ml) and hexane (5 ml) and pulled dry to give awhite solid (1.4 gm). The organic phase was washed with 2 molarhydrochloric acid (20 ml), water (20 ml) and brine (20 ml). Both thesolid product and organic phase were then analysed by GC. The product inboth solid form and in solvent solution had a ratio of(S)-α-cyano-3-phenoxybenzyl(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylateto (R)-α-cyano-3-phenoxybenzyl(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylateof 95:5.

EXAMPLE 3 Thermal Coupling of((1R,3S)-3-((Z)-2-Chloro-propenyl)-2,2-dimethyl-cyclopropanecarbonylchloride to (S)-3-phenoxybenzaldehyde cyanohydrin with DistillativeRemoval of HCl

The S-cyanohydrin (1 gm @ 90%=4 millimol) was charged to a clean dry 3necked round bottomed flask fitted with magnetic stirrer bar, short pathdistillation equipment (vented to a caustic scrubber system),thermometer and nitrogen blanket.

Cyclohexane (15 to 20 ml) was then added to the reactor agitation andthe nitrogen blanket started at 20° C. The S-cyanohydrin was a slurry inthe system at this temperature. The slurry was agitated and heated 80°C. until the cyclohexane started to distil. At this point the acidchloride (1.24 gm 4.8 millimol) dissolved in cyclohexane (15 ml) wasadded, dropwise, to the reactor over 1 hour trying to balance theaddition rate with the cyclohexane distillation rate. The addition ofthe acid chloride was sub-surface via a syringe pump fitted with aTeflon syringe. Once the addition was complete the distillation wascontinued replacing the distilled cyclohexane with fresh solvent.Reaction progress was monitored by GC. After completion of addition,there was 29 area % acid chloride, 24 area % cyanohydrin and 44 area %gamma-cyhalothrin present (96:4 ratio of α-S to α-R diastereomers).After 2.5 hours a further addition of S-cyanohydrin (0.1 gm=0.4millimol) was made and the distillation continued for a further 1 hrafter which time there was still 7.3 area % acid chloride remaining. Thereaction mass was then cooled to room temperature and left, withoutagitation, overnight under nitrogen. The following day the reaction masswas re-heated to 80° C. and a further addition of S-cyanohydrin (0.1gm=0.4 millimol) made followed by 3 hours of distillative reaction andfinally cooling and bottling off. Analysis of the reaction showed thatthe diastereoisomer ratio was 95:5.

EXAMPLE 4

Further runs were performed and the results are given in Table I. TABLEI Coupling of((1R,3S)-3-((Z)-2-Chloro-propenyl)-2,2-dimethyl-cyclopropanecarbonylchloride with (S)-3-phenoxybenzaldehyde cyanohydrin End of reactionProduct Acid Diastereo- Experiment Scale mmol Base/Buffer ReactionChloride isomer Number Acid Chloride Solvent (Base mol ratio) Temp ° C.Mode of addition and reaction times Area % Ratio 1 7.74 Toluene Pyridine(1:1) −10° C.  Acid chloride added to cyanohydrin and then 0 92.8 baseadded. 4 hrs after addition 88% complete. 2 2.14 Toluene Pyridine (1:1)−10° C.  Acid chloride added to cyanohydrin and then 0 92.5 base added.4 hrs after addition 87% complete. 3 19.1 Toluene Pyridine (1:1) −10°C.  Slow base addition to acid chloride + 0 95.5 cyanohydrin. 4 hrsafter addition 90% complete. 4 10.7 Toluene Pyridine (1:1) −10° C. Co-addition of acid chloride & base to 0.3 95.4 cyanohydrin. Reaction83% complete after 2 hrs. 5 21 Water NaOH/phosphate 10° C. Co-additionof cyanohydrin and acid chloride 6.8 92.9 with aqueous controlled at pH7 ± 1. Worked up after 1 hr 16.8% complete. 6 21 Hexane/ NaOH/phosphate10° C. Co-addition of cyanohydrin and acid chloride 20.7 88.7 water withaqueous controlled at pH 7 ± 1. Worked up after 1 hr 5.3% complete. 7152 Hexane/ Sodium tetra- 10° C. Co-addition of cyanohydrin and acidchloride 0.1 92.6 water borate (1.5) with aqueous at pH 9. Only 17.1%complete after 2 hrs. 8 20 Hexane/ NaOH 10° C. Co-addition ofcyanohydrin and acid chloride 27.4 44.4 water with aqueous controlled atpH 13. Worked up after 5 hrs 29.5% complete. 9 2.37 Toluene None 75° C.Reactants charged and heated to 75° C. 30.0 95.7 and stirred overnightsampling regularly. Worked up after 24 hrs 34.5% complete.In Experiments 1-2, the cyanohydrin had an S to S + R ratio of about 92and in Experiments 3-8 the ratio was 96.2

1. A process for the preparation of gamma-cyhalothrin comprising stepsof a) chlorinating 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid to give 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride and b) esterifying 1R cis-Z3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride with the (S)-cyanohydrin of3-phenoxy benzaldehyde (III).
 2. A process according to claim 1 in whichthe HCl formed during the esterification is removed from the reactionmass using a combination of physical methods and a sub-stoichiometricamount of a base.
 3. A process according to claim 2 in which the base isadded once the esterification reaction has been taken to greater than50% completion using only physical removal of the HCl.
 4. A processaccording to claim 2 in which the base is an organic base selected frompyridine, alkylpyridines, quinoline, the trimethylether oftriethanolamine or the mono-hydrochloride salt of DABCO, or an inorganicbase selected from an alkali metal carbonate or bicarbonate or alkalineearth metal oxide, hydroxide or carbonate or a combination of an organicand an inorganic base
 5. A process according to claim 4 in which thebase is a pyridine or an alkylpyridine.
 6. A process according to claim2 in which the esterification reaction is carried out in a solventselected from toluene, o-xylene, mixed xylenes or halobenzenes, forexample fluorobenzene, hexane, cyclohexane, iso-hexane, heptane, octaneor petroleum ethers.
 7. A process according to claim 6 in which thesolvent is hexane, cyclohexane, iso-hexane, heptane or octane.
 8. Aprocess according to claim 2 in which the esterification reaction iscarried out in a two-phase system in which one phase is an aqueousphase, optionally containing an organic base.